DESCRIPTION (provided by applicant: Despite prevention and intervention efforts, prevalence of cocaine (COC) use and dependence remains stable, which suggests innovative strategies are needed, like pharmacotherapy. COC blocks dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters. COC addiction is characterized by perturbations of these systems making monoamine uptake inhibition a logical target for medications development. Over 30 trials determined the efficacy of monoamine uptake inhibitors for COC dependence, but only DA-SERT and NET inhibitors were effective in a majority of the trials in which they were tested. Continuing to target monoamine uptake inhibition is warranted, but novel pharmacological strategies are needed to enhance efficacy. We propose to demonstrate the initial efficacy of an innovative pharmacological strategy for managing COC dependence: Triple Monoamine-Uptake Inhibition. Triple monoamine uptake inhibitors are under development, but are not yet available for use with humans. Triple monoamine-uptake inhibition can; however, be achieved by combining available medications. Duloxetine (DUL), an antidepressant, has high affinity for the SERT and NET (ki = 0.8 and 7.5 nM, respectively), but lower affinity for the DAT (ki = 240 nM). Methylphenidate (MTH) has high affinity for the DAT (ki = 34 nM), but lower affinity for the SERT and NET (ki = >10,000 and 339 nM, respectively). We will combine DUL and MTH to functionally produce a triple monoamine-uptake inhibitor. A mixed-model study will be conducted in which separate cohorts of non- treatment-seeking, COC-dependent participants will be randomized to different maintenance doses of delayed- release DUL (i.e., DUL dose is a between-subject factor). Participants (N=16) in each DUL cohort will be maintained concurrently on long-acting MTH (i.e., MTH dose is a within-subject factor). The reinforcing effects of COC will be determined after participants in each DUL cohort are maintained for 4 days on each of the MTH doses (i.e., COC dose is also a within-subject factor). COC self-administration will be the primary outcome measure because the ability to attenuate the reinforcing effects of drugs is a reliable predictor of an effective pharmacotherapy. We hypothesize DUL-MTH combinations will produce an additive or supra-additive reduction in the reinforcing effects of COC relative to the constituent drugs alone. Innovations include: 1) testing a novel strategy, triple monoamine-uptake inhibition; 2) testing a combination of marketed drugs as opposed to waiting for compounds under development to be available for use in humans, thereby quickly impacting clinical research; 3) the use of once-daily dosing formulations of DUL and MTH which will improve compliance when advanced to clinical trials; 4) the use of a sophisticated drug self-administration procedure; 5) testing multiple doses of DUL and MTH alone and in combination to identify the optimal dose combination to enhance the probability of success when advanced to a clinical trial; and 6) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of DUL-MTH combinations.